The present invention relates to novel substituted dimeric benzimidazoles useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention are dopaminergic agents useful as antipsychotic agents for treating psychoses such as schizophrenia.
Dopamine D2 antagonists are established as antipsychotic agents. More recently, the dopamine D3 receptor has been identified (Schwartz Jean-Charles, et al., The Dopamine D3 Receptor as a Target for Antipsychotics. In Novel Antipsychotic Drugs, Meltzer H. Y., Ed., Raven Press, New York, 1992, p. 135-144). On the basis of the localization of the dopamine D3 receptor in the limbic area of the brain, a selective D3 antagonist should show antipsychotic activity but not have the neurological side effects of D2 antagonists (Sokoloff P., et al., Molecular Cloning and Characterization of a Novel Dopamine Receptor (D.sub.3) as a Target for Neuroleptics, Nature, 347:146 (1990); Sokoloff P., et al., Localization and Function of the D.sub.3 Dopamine Receptor, Arzneim.-Forsch./Drug Res., 42(1):224, (1992)).
The compounds of the present invention are also useful for the treatment of disorders which respond to dopaminergic blockade which include psychotic depression, substance abuse (Caine S. B. and Koob G. F., Modulation of Cocaine Self-Administration in the Rat Through D-3 Dopamine Receptors, Science, 260:1814 (1993)), and compulsive disorders (Goodman W. K., et al., The role of serotonin and dopamine in the pathophysiology of obsessive compulsive disorder, International Clinical Psychopharmacology, 7(Supp. 1):35 (1992)).
We have surprisingly and unexpectedly found that a series of dimeric benzimidazoles are dopaminergic agents which bind selectively to the dopamine D3 receptor and are thus useful as antipsychotic agents for treating psychoses such as schizophrenia.